Ciprofloxacin and sparfloxacin penetration into human brain tissue and their activity as antagonists of GABAA receptor of rat vagus nerve

Davey, Peter; Charter, M. K.; Kelly, Shannon; Varma, T. R. K.; Jacobson, Ingemar; Freeman, Amanda; Precious, Elaine; Lambert, Jeremy J.

doi:10.1128/aac.38.6.1356

Cited by 29 publications

(17 citation statements)

References 10 publications

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“…Single gyrase mutants and the slow-accumulation mutant remained susceptible to sparfloxacin (MICs, Յ1.25 g/ml). This is within the range of the achievable concentrations of sparfloxacin in serum, which peaks at 1 to 2 g/ml after the administration of a 400-mg oral dose (9). The apparent requirement of at least two gyrase mutations for resistance to sparfloxacin (i.e., for MICs of 4 g/ml or higher, the clinical interpretative breakpoint for resistance to fluoroquinolones) suggests that it may be more difficult to select for resistant mutants with sparfloxacin than with other fluoroquinolones.…”

Section: Discussionsupporting

confidence: 55%

Gyrase mutations in laboratory-selected, fluoroquinolone-resistant mutants of Mycobacterium tuberculosis H37Ra

Kocagoz

Hackbarth

Ünsal

et al. 1996

Antimicrob Agents Chemother

110

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To characterize mechanisms of resistance to fluoroquinolones by Mycobacterium tuberculosis, mutants of strain H37Ra were selected in vitro with ofloxacin. Their quinolone resistance-determining regions for gyrA and gyrB were amplified and sequenced to identify mutations in gyrase A or B. Three types of mutants were obtained: (i) one mutant (TKp1) had no mutations in gyrA or gyrB; (ii) mutants that had single missense mutations in gyrA, and (iii) mutants that had two missense mutations resulting in either two altered gyrase A residues or an altered residue in both gyrases A and B. The TKp1 mutant had slightly reduced levels of uptake of [14C]norfloxacin, which was associated with two- to fourfold increases in the MICs of ofloxacin, ciprofloxacin, and sparfloxacin. Gyrase mutations caused a much greater increase in the MICs of fluoroquinolones. For mutants with single gyrA mutations, the increases in the MICs were 4- to 16-fold, and for mutants with double gyrase mutations, the MICs were increased 32-fold or more compared with those for the parent. A gyrA mutation in TKp1 secondary mutants was associated with 32- to 128-fold increases in the MICs of ofloxacin and ciprofloxacin compared with the MICs for H37Ra and an eight-fold increase in the MIC of sparfloxacin. Sparfloxacin was the most active fluoroquinolone tested. No sparfloxacin-resistant single-step mutants were selected at concentrations of > 2.5 micrograms/ml, and high-level resistance (i.e., MIC, > and = 5 micrograms/ml) was associated with two gyrase mutations. Mutations in gyrB and possibly altered levels of intracellular accumulation of drug are two additional mechanisms that may be used by M. tuberculosis in the development of fluoroquinolone resistance. Because sparfloxacin is more active in vitro and selection of resistance appears to be less likely to occur, it may have important advantage over ofloxacin or ciprofloxacin for the treatment of tuberculosis.

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Section: Discussionsupporting

confidence: 55%

Gyrase mutations in laboratory-selected, fluoroquinolone-resistant mutants of Mycobacterium tuberculosis H37Ra

Kocagoz

Hackbarth

Ünsal

et al. 1996

Antimicrob Agents Chemother

110

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“…observed following the administration of quinolones are related to the ability of these drugs to cross the blood-brain barrier (4,5,9). In our study, there was no evidence of any relationship between CNS-related side effects and CSF drug levels.…”

Section: Discussioncontrasting

confidence: 41%

“…Data on rufloxacin penetration into body fluids after a single oral administration have demonstrated a mean time to maximum drug concentration in plasma Ϯ standard deviation of 3.83 Ϯ 2.62 h (12) and mean times to maximum drug concentration in the extravascular compartment ranging from 3.5 to 11.8 h (26,28). Especially for drugs with long elimination half-lives, a delayed time to peak concentration in CSF was observed (5). Since rufloxacin has good lipophilicity and the longest half-life of any quinolone currently available, higher concentrations in CSF would have been found if a longer sampling time had been used.…”

Section: Discussionmentioning

confidence: 99%

Penetration of Rufloxacin into the Cerebrospinal Fluid in Patients with Inflamed and Uninflamed Meninges

Moretti

Pauluzzi

Cesana

2000

Antimicrob Agents Chemother

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Forty-four patients scheduled for lumbar puncture (LP) were recruited to determine the level of penetration of orally administered rufloxacin into cerebrospinal fluid (CSF). The patients were divided into three clinical groups: those with normal CSF (groups A 1d and A 7d ), those with aseptic meningitis (group B), and those with bacterial meningitis (group C). Members of group A 1d received a single 400-mg rufloxacin dose, while group A 7d , B, and C constituents had a multiple-dose regimen (one 400-mg dose, followed by one 200-mg dose daily for 6 days). LP was performed on group A 1d members 5 h after they had received treatment, while for group A 7d it was undertaken 5 h after administration of the last dose. For group B, LP was performed 5 h after the first and the last doses, whereas for group C it was undertaken after the first, fourth, and last doses. Concentrations of rufloxacin in simultaneously collected CSF and plasma samples were determined. Mean CSF/plasma rufloxacin concentration ratios ranged from 0.57 to 0.84, depending on the study group. A higher, but not statistically significant, degree of penetration into CSF was observed in patients with bacterial meningitis than in those with normal CSF or aseptic meningitis. These data indicate that rufloxacin diffuses efficiently into the CSF of patients with either inflamed or uninflamed meninges.Although the introduction of antibiotics made bacterial meningitis curable, the morbidity and mortality associated with this disease remain unacceptably high. In a recent review of 493 episodes of bacterial meningitis in adults, the overall case fatality rate was 25% (6).The penetration of an antibacterial drug into the cerebrospinal fluid (CSF) is an important characteristic in terms of its potential use in central nervous system (CNS) infections. In the presence of inflamed meninges, therapeutic concentrations of many antibiotics can be attained in CSF (2). However, in some persons with brain abscesses, early meningitis, or latestage meningitis, only minor impairments of the blood-CSF barrier occur. Dexamethasone, recommended for use in adjunctive therapy for bacterial meningitis, reduces meningeal inflammation (25) and thereby decreases drug penetration into CSF (2, 23). To ensure successful therapy and to prevent relapses, therapeutic concentrations of any antibiotic proposed for the treatment of CNS infections should be achieved even in the presence of uninflamed meninges.Fluoroquinolones are broad-spectrum antimicrobial agents with in vitro and in vivo bactericidal activity against susceptible organisms (10). The individual fluoroquinolones differ in their physiochemical properties, pharmacokinetic characteristics, and body fluid penetration abilities (10,14). Their lipophilicity (octanol-buffer partition coefficient ϭ 0.37 at pH 7) (1, 7) and the high apparent volume of distribution of 130 to 150 liters (12,15,26,28) account for their high degree of penetration into CSF. However, analysis of comparative data on CSF transport and disposition of quinolones ...

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“…Typical population ciprofloxacin tissue to plasma distribution coefficients (Kp) for 10 different tissues including lung, muscle, kidney and adipose were taken from clinical studies available in the literature and used as informative priors while estimating the tissue Kp values [25–32]. Kp values are determined from the ratio of total tissue and plasma concentrations and described according to Eq.…”

Section: Methodsmentioning

confidence: 99%

A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin: a step towards predicting bacterial killing at sites of infection

Sadiq

Nielsen

Khachman

et al. 2016

J Pharmacokinet Pharmacodyn

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The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model was built using a non-linear mixed effects approach based on data from 102 adult intensive care unit patients. Tissue to plasma distribution coefficients (Kp) were available from the literature and used as informative priors. The developed WB-PBPK model successfully characterized both the typical trends and variability of the available ciprofloxacin plasma concentration data. The WB-PBPK model was thereafter combined with a pharmacokinetic–pharmacodynamic (PKPD) model, developed based on in vitro time-kill data of ciprofloxacin and Escherichia coli to illustrate the potential of this type of approach to predict the time-course of bacterial killing at different sites of infection. The predicted unbound concentration–time profile in extracellular tissue was driving the bacterial killing in the PKPD model and the rate and extent of take-over of mutant bacteria in different tissues were explored. The bacterial killing was predicted to be most efficient in lung and kidney, which correspond well to ciprofloxacin’s indications pneumonia and urinary tract infections. Furthermore, a function based on available information on bacterial killing by the immune system in vivo was incorporated. This work demonstrates the development and application of a WB-PBPK–PD model to compare killing of bacteria with different antibiotic susceptibility, of value for drug development and the optimal use of antibiotics .Electronic supplementary materialThe online version of this article (doi:10.1007/s10928-016-9486-9) contains supplementary material, which is available to authorized users.

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Ciprofloxacin and sparfloxacin penetration into human brain tissue and their activity as antagonists of GABAA receptor of rat vagus nerve

Cited by 29 publications

References 10 publications

Gyrase mutations in laboratory-selected, fluoroquinolone-resistant mutants of Mycobacterium tuberculosis H37Ra

Gyrase mutations in laboratory-selected, fluoroquinolone-resistant mutants of Mycobacterium tuberculosis H37Ra

Penetration of Rufloxacin into the Cerebrospinal Fluid in Patients with Inflamed and Uninflamed Meninges

A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin: a step towards predicting bacterial killing at sites of infection

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